Gliomas are the most common central nervous system tumors. Glioblastoma multiforme (GM), the highest-grade malignant, grows very rapidly-sometimes doubling in size every 10 days- and is nearly uniformly fatal. GM tumors are generally treated by surgery followed by radiation. Although radiation therapy is the most effective postoperative adjuvant for GM, however, it has not substantially altered long-term disease control. The median survival of patients with GM has remained approximately 1 year, regardless of therapeutic approach.. The poor clinical outcome of patients with GM is associated with a characteristic in vivo and in vitro radioresistance of these brain tumors compared to other human neoplasms. Furthermore, although conventional synthetic radiosensitizing drugs can potentiate tumor-cell killing by radiation, undesirable normal tissue morbidity prevents repeated administration of the sensitizer and is thus a major obstacle to its use. Approaches that can enhance the radiosensitivity of such resistant tumor cells are much needed to reduce mortality in cancer patients. We discovered that berberine, a relatively non-toxic compound isolated from Chinese medicinal herbs, could enhance the radiation response of radioresistant human glioma cells in vitro. In addition, we showed that berberine could trigger an endogenous cell-suicide mechanisms, apoptosis, in GM tumor cells that express mutant p53, a genetic defect endogenous cell-suicide mechanism, apoptosis, in GM tumor cells that express mutant p53, a genetic defect thought to contribute to radioresistance in many cell types. We propose to extend these findings by comparing the efficacy of berberine with conventional radiosensitizers in cultures of GM tumor cells and normal human brain cells. In traditional Chinese Medical practice, herbs are nearly always prescribed in combination, with the intention of regulating the biological action of each individual herb. Thus, our second aim is to determine whether the effect of berberine, as a radiosensitizer, can be enhanced by combining it with other herbal compounds. Our third aim is to determine the mechanisms of radiosensitization by berberine and by any optimal combination treatments discovered.. Cellular and molecular pathways mediating radiosensitization will be evaluated by time-lapse video microscopy and nucleic acid array-based gene expression analysis. These studies represent an initial step toward the clinical goal of providing improved multi-modality radiotherapy for patients with gliomas. In addition, because more than half of adult malignancies and high-grade pediatric brain tumors harbor p53 mutations, important clinical applications may emerge from the elucidation of p53-independent mechanisms of apoptosis.